WO2020224609A1 - 激酶抑制剂的用途 - Google Patents

激酶抑制剂的用途 Download PDF

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WO2020224609A1
WO2020224609A1 PCT/CN2020/088874 CN2020088874W WO2020224609A1 WO 2020224609 A1 WO2020224609 A1 WO 2020224609A1 CN 2020088874 W CN2020088874 W CN 2020088874W WO 2020224609 A1 WO2020224609 A1 WO 2020224609A1
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heterocyclic group
membered
crystal form
compound
nitrogen
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PCT/CN2020/088874
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English (en)
French (fr)
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郭霞
李彤
王静
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山东轩竹医药科技有限公司
轩竹生物科技有限公司
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Priority to CN202080033803.0A priority Critical patent/CN113811302B/zh
Publication of WO2020224609A1 publication Critical patent/WO2020224609A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a new use of a CDK4/6 kinase inhibitor and a pharmaceutically acceptable salt or crystal form thereof in the preparation of a medicine for treating thymoma.
  • Thymoma is a rare tumor, but it is the most common primary tumor of the anterior superior mediastinum, accounting for about 20%-40% of all mediastinal tumors in adults. Thymomas originate from the thymic epithelium, and most of them are located in the anterior mediastinum. It is attached to the pericardium and is closely related to the large blood vessels in the mediastinum. A few occur outside the mediastinum. Thymomas grow slowly and are considered to grow painlessly, but are clinically potentially invasive and easily infiltrate surrounding tissues and organs. Patients with thymoma usually present with chest pain, dyspnea, superior vena cava syndrome, and pericardial tamponade.
  • Thymoma is closely related to autoimmune disorders, and is often accompanied by paraneoplastic syndromes such as myasthenia gravis (MG), various granulocytopenias, red blood cell dysplasia, hypogammaglobulinemia, and collagen angiopathy. syndromes).
  • MG myasthenia gravis
  • granulocytopenias red blood cell dysplasia
  • hypogammaglobulinemia angiopathy. syndromes
  • Foreign literature shows that the annual incidence of thymoma in the population is 0.15/100,000, the ratio of male to female is 1:1, and the peak age of incidence is 40-50 years old. The incidence of thymoma with myasthenia gravis is about 10% to 46%, mostly between 30 and 40 years old. Thymomas in children are rare but more malignant.
  • Surgical resection is the main method for the treatment of early thymoma.
  • radiotherapy and chemotherapy can be used as auxiliary and palliative methods.
  • Thymoma is relatively sensitive to chemotherapy.
  • cisplatin such as cisplatin and doxorubicin combined chemotherapy or doxorubicin, cisplatin, vincristine, cyclophosphamide combined chemotherapy, but chemotherapy Will bring huge side effects to patients. Therefore, various pharmaceutical companies are committed to the development of high-efficiency and low-toxicity small molecule drugs. At present, there is no specific small molecule therapeutic drug for the treatment of thymoma, and there is an unmet drug demand in this therapeutic field.
  • PCT/CN2014/095615 discloses a series of CDK4/6 kinase inhibitors. Studies have shown that its compounds have excellent CDK4/6 kinase inhibitory activity, show good blood-brain barrier permeability, provide the possibility for CDK inhibitors as tumor treatments, and have good safety.
  • the inventor unexpectedly discovered that the compound of formula (I') has a good therapeutic effect on thymoma and can significantly reduce the volume of the tumor, which indicates that the compound of formula (I') is expected to be a therapeutic Specific medicine for thymoma.
  • the present invention relates to a new application of a compound of formula (I'), its pharmaceutically acceptable salt or its crystal form in the preparation of a medicine for treating thymoma.
  • the present invention provides a use of a compound of formula (I'), a pharmaceutically acceptable salt or crystal form thereof in the preparation of a medicament for the treatment of thymoma,
  • a 1 and A 2 are each independently nitrogen;
  • R 1 is selected from C 1-6 alkyl
  • R 2 is selected from C 1-6 alkyl
  • R 3 and R 5 are each independently selected from halogen or hydrogen, and at least one of R 3 and R 5 is halogen;
  • R 4 is selected from 5-6 membered nitrogen-containing heterocyclic group optionally substituted by Q 2 , 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro Heterocyclic group;
  • Q 2 is selected from amino, hydroxy, halo, trifluoromethyl, cyano, C 1-6 alkoxy, di-C 1-6 alkylamino group, or an optionally substituted C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group or 7-9 membered bridged heterocyclic group, the substituent is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C 1-6 alkane Group, C 1-6 alkoxy, 3-6 membered cycloalkyl;
  • n is selected from 0,1.
  • a 1 and A 2 are each independently nitrogen;
  • R 1 is selected from C 1-4 alkyl
  • R 2 is selected from C 1-4 alkyl
  • R 3 and R 5 are each independently selected from halogen
  • R 4 is selected from 5-6 membered nitrogen-containing heterocyclic group optionally substituted by Q 2 , 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro Heterocyclic group,
  • Q 2 is selected from amino, hydroxy, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, 5-6 membered heterocyclic group or 7-9 membered bridged heterocyclic group.
  • a 1 and A 2 are each independently nitrogen;
  • R 1 is isopropyl
  • R 2 is methyl
  • R 3 and R 5 are each fluorine
  • R 4 is selected from 5-6 membered nitrogen-containing heterocyclic groups optionally substituted by Q 2 , wherein Q 2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkane Oxy, 6-membered heterocyclic group or 8-membered bridged heterocyclic group.
  • R 4 is selected from a 5-6 membered nitrogen-containing heterocyclic group containing 1-2 nitrogen atoms optionally substituted by Q 2 , and the 5-6 membered nitrogen-containing heterocyclic group is connected to the general formula (I”) via the nitrogen atom the methylene linking, wherein Q 2 is selected from amino, hydroxy, trifluoromethyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, or 8-membered nitrogen-containing bridged heterocyclic group.
  • R 4 is selected from optionally substituted by Q 2 Wherein Q 2 is selected from a C 1-4 alkyl group or an 8-membered nitrogen-containing bridged heterocyclic group.
  • the compound of formula (I') is selected from:
  • the compound is selected from the following compounds (Compound 1) or a pharmaceutically acceptable salt or crystal form thereof:
  • the crystal form is the free crystal form of compound 1.
  • the crystalline form is the free crystal form A of compound 1, and the crystalline form A uses Cu-K ⁇ radiation to express the X-ray powder diffraction pattern at 6.6 ⁇ There are characteristic peaks at 0.2°, 10.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 17.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, and 20.6 ⁇ 0.2°.
  • the crystal form is the free crystal form A of compound 1, and the crystal form A uses Cu-K ⁇ radiation to express the X-ray powder diffraction pattern at 6.6 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 30.4 ⁇ There is a characteristic peak at 0.2°.
  • the crystal form is the free crystal form A of compound 1, and the crystal form A uses Cu-K ⁇ radiation to express the X-ray powder diffraction pattern at 6.6 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.1 ⁇ There are characteristic peaks at 0.2°, 20.6 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 25.9 ⁇ 0.2°, 28.1 ⁇ 0.2°, 30.4 ⁇ 0.2°.
  • the crystal form is the free crystal form A of compound 1, and the crystal form A has an X-ray powder obtained by using Cu-K ⁇ radiation as shown in FIG. Diffraction pattern.
  • the crystal form is that of a salt of compound 1.
  • the crystal form is the maleate salt crystal form of Compound 1.
  • the crystalline form is the crystalline form of compound 1 dimaleate.
  • the thymoma is advanced and/or metastatic thymoma.
  • the thymoma is locally advanced, advanced and/or metastatic thymoma.
  • the thymoma is a thymoma that has failed other anti-tumor treatments.
  • the other anti-tumor treatment is selected from surgical treatment, radiotherapy, chemotherapy, immunotherapy, and the use of compounds other than the compound of formula (I'), its pharmaceutically acceptable salt and its crystal form One or more of targeted therapies performed by targeted drugs.
  • the thymoma patient carries a GTF2I oncogene point mutation.
  • the thymoma is selected from benign thymoma and thymic carcinoma.
  • the thymoma is thymic carcinoma.
  • the thymic cancer is selected from the following subtypes: thymic squamous cell carcinoma, thymic basal cell carcinoma, mucoepidermoid carcinoma, sarcomatoid carcinoma, adenocarcinoma, NUT carcinoma.
  • the thymoma is selected from the following subtypes: type A, type AB, type B1, type B2 and type B3.
  • the compound of formula (I'), its pharmaceutically acceptable salt, or crystalline form thereof is administered alone or in combination with one or more other therapeutic agents.
  • the other therapeutic agent is selected from the group consisting of antimetabolites and antitumor drugs, growth factor inhibitor antitumor drugs, antibody antitumor drugs, mitotic inhibitor antitumor drugs, hormonal antitumor drugs, alkylating agents Antitumor drugs, metal platinum antitumor drugs, topoisomerase inhibitor antitumor drugs, immunosuppressive antitumor drugs, purine analogue antitumor drugs, antibiotic antitumor drugs, kinase inhibitor antitumor drugs, targets To therapeutic drugs.
  • the present invention also provides the use of a pharmaceutical composition, the composition comprising a compound of formula (I'), a pharmaceutically acceptable salt or crystal form thereof, and a pharmaceutically acceptable carrier, and optionally, further comprising One or more other therapeutic agents.
  • the other therapeutic agent is selected from the group consisting of antimetabolites and antitumor drugs, growth factor inhibitor antitumor drugs, antibody antitumor drugs, mitotic inhibitor antitumor drugs, hormonal antitumor drugs, alkylating agents Antitumor drugs, metal platinum antitumor drugs, topoisomerase inhibitor antitumor drugs, immunosuppressive antitumor drugs, purine analogue antitumor drugs, antibiotic antitumor drugs, kinase inhibitor antitumor drugs, targets To therapeutic drugs.
  • the crystalline form is selected from the free body crystalline form of the compound of formula (I').
  • halogen in the present invention includes, for example, fluorine, chlorine, bromine and iodine.
  • C 1-6 alkyl group in the present invention can be linear or branched, including, for example, "C 1-4 alkyl group", "C 1-3 alkyl group", etc. Specific examples thereof include but are not limited to :Methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methyl Butyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,3-dimethylbutylbutyl, 2-ethylbutyl,
  • C 1-6 alkoxy, di-C 1-6 alkylamino in the present invention refers to the formation of C 1-6 alkyl-O-, (C 1-6 alkyl) 2 -N-
  • the group of "C 1-6 alkyl” is as defined above.
  • C 1-4 alkoxy, di-C 1-4 alkylamino in the present invention means that it is formed in the manner of C 1-4 alkyl-O-, (C 1-4 alkyl) 2 -N-
  • the group of "C 1-4 alkyl” is as defined above.
  • the "3-6 membered cycloalkyl group” in the present invention refers to a cyclic alkyl group derived from an alkane of 3-6 carbon atoms by removing one hydrogen atom, including, for example, "3-5 membered cycloalkyl group", “ 4-6 membered cycloalkyl”, “5-6 membered cycloalkyl” and the like. Examples thereof include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane and the like.
  • the "3-6 membered heterocyclic group” in the present invention refers to at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3-6
  • the saturated or partially saturated and non-aromatic cyclic group, the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the cyclic structure (such as a carbon atom, nitrogen Atom or sulfur atom) can be oxo, including, for example, "5-6 membered heterocyclic group", "5-6 membered nitrogen-containing heterocyclic group", “6 membered heterocyclic group", "6 membered nitrogen-containing heterocyclic group" "Wait.
  • "linked to the methylene group in the general formula (I") through a nitrogen atom” refers to a nitrogen-containing group (for example, a nitrogen-containing heterocyclic group, such as a "5-6 membered nitrogen-containing heterocyclic group” Or “6-membered nitrogen-containing heterocyclic group”; nitrogen-containing fused heterocyclic group, such as “6-10 membered nitrogen-containing fused heterocyclic group”; nitrogen-containing bridged heterocyclic group, such as "7-9 membered nitrogen-containing heterocyclic ring Group” or "8-membered nitrogen-containing bridged heterocyclic group”; nitrogen-containing spiro heterocyclic group, such as "7-11 membered nitrogen-containing spiro heterocyclic group”) is connected to a methylene group through a nitrogen atom.
  • a nitrogen-containing heterocyclic group for example, a nitrogen-containing heterocyclic group, such as a "5-6 membered nitrogen-containing heterocyclic group” Or “6-membered nitrogen-containing hetero
  • the fused ring described in the present invention refers to a fused ring structure formed by two or more ring structures that share two adjacent atoms (that is, share a bond) connected to each other.
  • the bridged ring in the present invention refers to a bridged ring structure formed by two or more ring structures sharing two non-adjacent carbon atoms connected to each other.
  • the spiro ring in the present invention refers to a spiro ring structure formed by connecting two or more cyclic structures sharing one carbon atom.
  • the "6-10 membered fused heterocyclic group" mentioned in the present invention means that two or more ring structures share two adjacent atoms (that is, share a bond) and are connected to form at least one heteroatom.
  • the fused ring structure of 6-10 ring atoms includes, for example, "6-10 membered nitrogen-containing fused heterocyclic group” and the like.
  • the "7-9-membered bridged heterocyclic group” in the present invention refers to a bridged ring structure of 7-9 ring atoms containing at least one heteroatom formed by sharing two non-adjacent atoms between any two rings.
  • the heteroatom is selected from N, S, O, CO, SO, and/or SO 2 and the like.
  • the "7-11 membered spiro heterocyclic group” in the present invention refers to a spiro ring structure with at least one heteroatom and at least one heteroatom formed by sharing one atom of at least two rings.
  • the heteroatom Selected from N, S, O, CO, SO and/or SO 2 and so on.
  • the molecular ratio of the compound of formula (I') to the corresponding alkali metal, other metals, organic base, inorganic acid, and organic acid can be any value.
  • the "pharmaceutical composition" of the present invention is any pharmaceutically acceptable dosage form, and is administered to patients in need of it by oral, parenteral, rectal or pulmonary administration.
  • oral administration When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration it can be made into injections, including injection, sterile powder for injection and concentrated solution for injection. When preparing the injection, it can be produced by the conventional method in the current pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. When used for rectal administration, it can be made into suppositories. When used for pulmonary administration, it can be made into inhalants or sprays.
  • the pharmaceutically acceptable carriers include, but are not limited to: fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, surfactants, preservatives, coloring agents, flavoring agents, Fragrance, effervescent, emulsifier, flocculant, deflocculant, bacteriostatic agent, solubilizer.
  • the tumor, cancer or cancer described in the present invention also includes metastasis in the primary organ, tissue and/or any other location, regardless of the location of tumor metastasis.
  • the failure of other anti-tumor therapies in the present invention refers to the use of other anti-tumor therapies, disease progression or intolerance.
  • the "thymoma” of the present invention includes type A, type AB, type B1, type B2, and type B3 according to the World Health Organization (WHO) classification (fourth edition in 2015).
  • WHO World Health Organization
  • the "thymic carcinoma” of the present invention is divided into the following subtypes according to the WHO classification (fourth edition in 2015): thymic squamous cell carcinoma, thymic basal cell carcinoma, mucoepidermoid carcinoma, sarcomatoid carcinoma, glandular carcinoma Cancer, NUT cancer, etc.
  • the thymic carcinoma of the present invention includes malignant thymoma.
  • the "chemotherapy” in the present invention is an abbreviation for chemotherapy. It mainly uses chemotherapy drugs to kill cancer cells to achieve the purpose of treatment.
  • the chemical drugs used are mainly cytotoxic drugs.
  • the "radiotherapy” in the present invention refers to a tumor treatment method, namely tumor radiotherapy, which mainly uses radiation for local tumor treatment.
  • the "radiation” includes ⁇ , ⁇ , ⁇ rays and various x-rays produced by radioisotopes. X-rays, electron beams, proton beams and other particle beams produced by radiotherapy machines or accelerators.
  • targeted therapy in the present invention refers to a method in which targeted drugs perform targeted and precise therapy by identifying specific proteins of tumor cells.
  • the "immunotherapy” in the present invention refers to a treatment method that controls or eliminates tumor cells by activating the immune system in the body.
  • the subject or patient can be any animal, preferably a mammal, such as bovine, equine, sheep, swine, canine, feline, rodent, and Long animals.
  • a particularly preferred subject is a human.
  • the "QD" in the present invention means administration once a day.
  • the present invention also provides a method for treating thymoma, which comprises administering a therapeutically effective amount of a compound of formula (I'), a pharmaceutically acceptable salt or crystal form thereof to a patient in need of such treatment, which can be obtained by methods known in the art Administer in any conventional and acceptable manner, and the therapeutically effective amount depends on the patient’s race, gender, age, weight, medical condition, type of disease, severity of disease, route of administration and related health conditions, and known to those skilled in the art Adjust other factors.
  • a “therapeutically effective amount” as used herein refers to an amount sufficient to cure or at least partially prevent the disease and its complications in patients who have already suffered from the disease. It is completely within the abilities of those skilled in the art to determine such an effective amount. For example, the effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient’s own immune system, the patient’s general conditions such as age, weight, and sex, the way the drug is administered, and other treatments that are simultaneously administered and many more.
  • the present invention also provides a composition of a compound of formula (I') and one or more other therapeutic agents, which can be administered simultaneously or sequentially with the compound of formula (1) for the treatment of patients with thymoma.
  • Figure 1 CT radiographic image of compound 1 before treatment.
  • Figure 2 CT radiograph after taking Compound 1 for eight cycles (about eight months).
  • Figure 3 The percentage change in the size of the target lesion tumor after taking compound 1, the abscissa represents the time (the number of days in the experimental study), where C3D1 represents the first day of the third cycle, C5D1 represents the first day of the fifth cycle, and so on, for each administration
  • the period is about 28 days, which specifically corresponds to the dosing regimen in the experimental example; the ordinate is the percentage change in tumor volume.
  • Fig. 4 X-ray powder diffraction pattern (XRPD pattern) of compound 1 crystal form A, the ordinate represents the diffraction intensity (intensity), and the abscissa represents the diffraction angle (2 ⁇ ).
  • the crystal form A of compound 1 is the crystal form A of the compound of formula (I) in the specification of the patent application PCT/CN2018/124418, and the content related to the preparation method is cited in this specification.
  • the crystalline form A of compound 1 mentioned in this application its parameter characterization, property test and other related content, please refer to patent application PCT/CN2018/124418, and it is cited herein.
  • Preparation method 1 Take 5.0g of compound 1, add 75mL of acetone, dissolve under magnetic stirring, and immediately precipitate a white solid. After stirring for 5 hours, suction filter to obtain a white powder. After vacuum drying at 35°C for 16 hours, the obtained solid is tested by XRPD and is crystalline. Type A.
  • Preparation method 2 Take 500 mg of compound 1, add 15 mL of isopropanol, stir in an oil bath at 80°C, dissolve and become clear (within 4.0h), naturally drop to room temperature (32°C), precipitate a white solid, continue stirring at room temperature for 12h After cooling to 15°C and stirring for 4.0h, suction filtration, the obtained solid was vacuum dried at 45°C for 16h, and analyzed by XRPD and 1 H-NMR, the obtained solid was crystal form A.
  • Preparation method 3 Take 5.0 g of compound 1 in a 100 mL three-necked flask, add 75 mL of sec-butanol, control the temperature in an oil bath to 95°C, and mechanically stir for 0.5 h to dissolve and become clear. Then, the temperature was lowered to 70°C in the oil bath, and about 25mg of seed crystals (that is, the crystal form A obtained in the preparation method 1 and 2) were added, and a white solid began to slowly precipitate. Continue to cool to 60°C in the oil bath.
  • the instrument used Bruker D2 X-ray powder diffractometer.
  • X-ray parameters Cu, K ⁇ ; incident slit: 0.6mm; divergence slit: 1mm; scanning mode: continuous; scanning range: 3.0-45.0 degrees; sampling step: 0.02 degrees; scanning time per step: 19.8s; detection Angle of the device: 2.0 degrees.
  • the X-ray powder diffraction diagram of the crystalline form A of compound I is shown in Figure 4.
  • the crystalline form has peaks at the following diffraction 2 ⁇ angles: 6.6 ⁇ 0.2°, 8.7 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.9 ⁇ 0.2° , 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.3 ⁇ 0.2° , 24.0 ⁇ 0.2°, 25.9 ⁇ 0.2°, 28.1 ⁇ 0.2°, 30.4 ⁇ 0.2°.
  • Compound 1 crystal form A tablet Add appropriate excipients to compound 1 crystal form A to prepare tablets of certain specifications.
  • the subject must have at least one measurable lesion that meets the definition of RECIST v1.1;
  • the ECOG score is 0 ⁇ 1;
  • ⁇ Blood routine absolute neutrophil count ⁇ 2.0 ⁇ 10 9 /L (or greater than the lower limit of the normal value of the research center laboratory), platelet count ⁇ 100 ⁇ 10 9 /L, hemoglobin ⁇ 100g/L;
  • ⁇ Liver function serum total bilirubin ⁇ 1.5 times the upper limit of the standard value (ULN), AST and ALT ⁇ 1.5 times ULN;
  • the expected life span of the subject is ⁇ 12 weeks
  • PET-CT examination showed that the left pleura was thickened frequently with increased metabolic activity, and multiple plaques in both lungs Film spots and micro nodules.
  • a needle biopsy of the pleural mass showed: Type B1 (lymphocyte-rich type) thymoma.
  • thymoma On July 31, he underwent thoracoscopic-assisted left thoracotomy, thymoma resection, left upper lobe wedge resection, partial pericardectomy, pleural peeling, and closed thoracic drainage.
  • Postoperative pathology Thymoma, type B2, invaded the parietal layer of the pericardium, lung tissue, and the visceral layer, parietal layer, and pleura of the diaphragm.
  • Postoperative adjuvant Paclitaxel and Loplatin were given 4 cycles of postoperative adjuvant chemotherapy from September 16th to December 10th, 2015. On April 13th and May 17th, 2018, two cycles of paclitaxel+cisplatin+recombinant human endostatin chemotherapy were performed.
  • the baseline check before enrollment was improved on July 19, 2018.
  • the enhanced CT scan of the chest, abdomen and pelvis showed: thymoma, pleural exfoliation changes after surgery; left anterior upper mediastinal soft tissue density shadow; two lung infectious lesions; ECOG score ⁇ 1, estimated by the investigator, the expected survival period ⁇ 12 weeks;
  • the results of physical examination, electrocardiogram, echocardiogram and laboratory safety examinations all met the standards.
  • the treatment process has undergone 3 dose increases.
  • the current dose is 320mg QD.
  • the patient has been stable for 12 months, and as shown in Figure 3, at the end of the 12th cycle of dosing, the tumor meridian has been reduced by 38.6% from baseline, and the target lesion has reached the standard of partial remission (PR) .
  • PR partial remission

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Abstract

一种CDK4/6激酶抑制剂的用途。具体地涉及式(I')所示化合物、其药学上可接受的盐或其晶型在制备用于治疗胸腺瘤的药物中的用途。

Description

激酶抑制剂的用途 1、技术领域
本发明属于医药领域，具体涉及一种CDK4/6激酶抑制剂及其药学上可接受盐或其晶型在制备用于治疗胸腺瘤的药物中的新用途。
2、背景技术
胸腺瘤是一种罕见的肿瘤，却是最常见的前上纵隔原发性肿瘤，约占成人所有纵膈肿瘤的20％-40％，胸腺瘤起源于胸腺上皮，绝大多数位于前纵隔，附着于心包，与纵隔内大血管关系密切，少数发生在纵膈以外部位。胸腺瘤生长缓慢，被认为无痛生长，但临床上有潜在的侵袭性，易浸润周围组织和器官。胸腺瘤患者通常在症状上表现为胸痛、呼吸困难、上腔静脉综合征、心包填塞等。胸腺瘤与自身免疫紊乱密切相关，常伴有重症肌无力(mysasthenia gravis，MG)、各类粒细胞减少症、红细胞发育不良、低丙种球蛋白血症、胶原血管病等副瘤综合征(paraneoplastic syndromes)。国外文献显示胸腺瘤在人群中的年发病率是0.15/10万，男女比例为1：1，发病高峰年龄在40～50岁。胸腺瘤伴发重症肌无力的发生率约为10％～46％，多在30～40岁。儿童胸腺瘤罕见，但恶性程度更高。
胸腺瘤的发病机制目前尚不清楚。有学者认为患者既往有放射治疗和EB病毒感染史可能与胸腺瘤有关。手术切除是早期胸腺瘤治疗的主要方法，对于不能手术或局部晚期胸腺癌患者，放射疗法和化学治疗可以作为辅助和姑息方法。胸腺瘤对化疗相对较敏感，目前大多采用含顺铂的联合化疗方案，如顺铂和多柔比星联合化疗或多柔比星、顺铂、长春新碱、环磷酰胺联合化疗，但是化疗会给患者带来巨大的副作用。因此，各医药公司都在致力于研发高效低毒的小分子药物。目前，胸腺瘤的治疗还没有特效的小分子治疗药物，该治疗领域存在未被满足的药物需求。
PCT/CN2014/095615公开了一系列CDK4/6激酶抑制剂。研究表明，其化合物具有优异的CDK4/6激酶抑制活性，显示出良好的血脑屏障通过性，为CDK抑制剂作为肿瘤的治疗提供了可能性，且具有良好的安全性。
Figure PCTCN2020088874-appb-000001
然而，该专利没有公开化合物对于胸腺瘤的治疗作用。
在对上述专利化合物进行研究的过程中，发明人意外地发现，式(I’)化合物对于胸腺瘤具有良好的治疗作用，可以明显缩小肿瘤的体积，这表明式(I’)化合物有望成为治疗胸腺瘤的特效药物。
3、发明内容
本发明涉及式(I’)化合物、其药学上可接受的盐或其晶型在制备用于治疗胸腺瘤的药物中的新应用。
本发明的技术方案如下所示：
本发明提供了一种式(I’)化合物、其药学上可接受的盐或其晶型在制备用于治疗胸腺瘤的药物中的用途，
Figure PCTCN2020088874-appb-000002
其中，
A 1和A 2分别独立地为氮；
R 1选自C 1-6烷基；
R 2选自C 1-6烷基；
R 3和R 5分别独立地选自卤素或氢，且R 3和R 5至少一个为卤素；
R 4选自任选被Q 2取代的5-6元含氮杂环基、6-10元含氮稠杂环基、7-9元含氮桥杂环基或7-11元含氮螺杂环基；
Q 2选自氨基，羟基，卤素，三氟甲基，氰基，C 1-6烷氧基，二C 1-6烷基氨基，或任选被取代基取代的C 1-6烷基、3-6元环烷基、3-6元杂环基或7-9元桥杂环基，所述取代基选自氨基、羟基、卤素、三氟甲基、氰基、C 1-6烷基、C 1-6烷氧基、3-6元环烷基；
n选自0、1。
在某些实施方案中，其中所述化合物具有下述式(I”)的结构，
Figure PCTCN2020088874-appb-000003
其中，
A 1和A 2分别独立地为氮；
R 1选自C 1-4烷基；
R 2选自C 1-4烷基；
R 3和R 5分别独立地选自卤素；
R 4选自任选被Q 2取代的5-6元含氮杂环基、6-10元含氮稠杂环基、7-9元含氮桥杂环基或7-11元含氮螺杂环基，
Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基、5-6元杂环基或7-9元桥杂环基。
在某些实施方案中，
A 1和A 2分别独立地为氮；
R 1为异丙基；
R 2为甲基；
R 3和R 5各自是氟；
R 4选自任选被Q 2取代的5-6元含氮杂环基，其中Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基、6元杂环基或8元桥杂环基。
在某些实施方案中，
R 4选自任选被Q 2取代的含1-2个氮原子的5-6元含氮杂环基，所述5-6元含氮杂环基通过氮原子与通式(I”)中的亚甲基连接，其中Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基或8元含氮桥杂环基。
在某些实施方案中，
R 4选自任选被Q 2取代的
Figure PCTCN2020088874-appb-000004
其中Q 2选自C 1-4烷基或8元含氮桥杂环基。
在某些实施方案中，其中所述的式(I’)化合物选自：
Figure PCTCN2020088874-appb-000005
Figure PCTCN2020088874-appb-000006
Figure PCTCN2020088874-appb-000007
Figure PCTCN2020088874-appb-000008
在某些实施方案中，所述化合物选自如下所示化合物(化合物1)或其药学上可接受的盐或其晶型：
Figure PCTCN2020088874-appb-000009
在本发明的某些实施方案中，所述的晶型为化合物1的游离体晶型。
在本发明的某些实施方案中，所述的晶型为化合物1的游离体晶型A，所述晶型A 在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱在6.6±0.2°、10.0±0.2°、13.2±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°处有特征峰。
在本发明的某些实施方案中，所述的晶型为化合物1的游离体晶型A，所述晶型A在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°、30.4±0.2°处有特征峰。
在本发明的某些实施方案中，所述的晶型为化合物1的游离体晶型A，所述晶型A在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°处有特征峰。
在本发明的某些实施方案中，所述的晶型为化合物1的游离体晶型A，所述晶型A具有基本上如图4所示的使用Cu-Kα辐射获得的X-射线粉末衍射图。
在本发明的某些实施方案中，所述的晶型为化合物1的盐的晶型。
在本发明的某些实施方案中，所述的晶型为化合物1的马来酸盐晶型。
在本发明的某些实施方案中，所述的晶型为化合物1的二马来酸盐晶型。
在某些实施方案中，所述的胸腺瘤为晚期和/或转移性胸腺瘤。
在某些实施方案中，所述的胸腺瘤为局部晚期、晚期和/或转移性胸腺瘤。
在某些实施方案中，所述的胸腺瘤为其他抗肿瘤治疗失败的胸腺瘤。
在某些实施方案中，所述的其他抗肿瘤治疗选自手术治疗，放疗，化疗，免疫治疗，以及采用除式(I’)化合物、其药学上可接受的盐和其晶型之外的靶向药物所进行的靶向治疗中的一种或多种。
在某些实施方案中，所述胸腺瘤患者携带GTF2I癌基因点突变。
在某些实施方案中，所述的胸腺瘤选自良性胸腺瘤和胸腺癌。
在某些实施方案中，所述胸腺瘤为胸腺癌。
在某些实施方案中，所述胸腺癌选自以下亚型：胸腺鳞状细胞癌，胸腺基底细胞样癌，粘液表皮样癌，肉瘤样癌，腺癌，NUT癌。
在某些实施方案中，所述的胸腺瘤选自以下亚型：A型、AB型、B1型、B2型和B3型。
在某些实施方案中，式(I’)化合物、其药学上可接受的盐或其晶型单独施用或与一种或多种其他治疗剂组合施用。
在某些实施方案中，其他治疗剂选自抗代谢物抗肿瘤药、生长因子抑制剂抗肿瘤药、抗体类抗肿瘤药、有丝分裂抑制剂抗肿瘤药、激素类抗肿瘤药、烷化剂类抗肿瘤药、金属铂类 抗肿瘤药、拓扑异构酶抑制剂抗肿瘤药、免疫抑制类抗肿瘤药、嘌呤类似物抗肿瘤药、抗生素类抗肿瘤药、激酶抑制剂类抗肿瘤药、靶向治疗药物。
本发明还提供了一种药物组合物的用途，所述组合物包括式(I’)化合物、其药学上可接受的盐或其晶型与药学上可接受的载体，任选地，还包括一种或多种其他治疗剂。
在某些实施方案中，其他治疗剂选自抗代谢物抗肿瘤药、生长因子抑制剂抗肿瘤药、抗体类抗肿瘤药、有丝分裂抑制剂抗肿瘤药、激素类抗肿瘤药、烷化剂类抗肿瘤药、金属铂类抗肿瘤药、拓扑异构酶抑制剂抗肿瘤药、免疫抑制类抗肿瘤药、嘌呤类似物抗肿瘤药、抗生素类抗肿瘤药、激酶抑制剂类抗肿瘤药、靶向治疗药物。
在某些实施方案中，所述的晶型选自式(I’)化合物的游离体晶型。
4、发明详述
本发明所述的“卤素”包括例如氟、氯、溴和碘。
本发明所述的“C 1-6烷基”可以为直链或支链状，包括例如“C 1-4烷基”、“C 1-3烷基”等，其具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“C 1-6烷氧基、二C 1-6烷基氨基”是指以C 1-6烷基-O-、(C 1-6烷基) 2-N-方式形成的基团，其中“C 1-6烷基”的定义如前文所述。
本发明所述的“C 1-4烷氧基、二C 1-4烷基氨基”是指以C 1-4烷基-O-、(C 1-4烷基) 2-N-方式形成的基团，其中“C 1-4烷基”的定义如前文所述。
本发明所述的“3-6元环烷基”，是指3-6个碳原子的烷烃部分去除一个氢原子衍生的环状烷基，包括例如“3-5元环烷基”、“4-6元环烷基”、“5-6元环烷基”等。其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基等。
本发明所述的“3-6元杂环基”，是指至少含有一个杂原子(例如含有1个、2个、3个、4个或5个)的且环原子数为3-6个的饱和或部分饱和的且不具有芳香性的环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代，包括例如“5-6元杂环基”、“5-6元含氮杂环基”、“6元杂环基”、“6元含氮杂环基”等。具体实例包括但不仅限于：1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二 氢噻唑基、哌啶基、哌嗪基、吗啉基、六氢嘧啶基、六氢哒嗪基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等，优选为“5-6元含氮杂环基”。
本发明所述的“通过氮原子与通式(I”)中的亚甲基连接”是指含氮基团(例如，含氮杂环基，如“5-6元含氮杂环基”或“6元含氮杂环基”；含氮稠杂环基，如“6-10元含氮稠杂环基”；含氮桥杂环基，如“7-9元含氮桥杂环基”或“8元含氮桥杂环基”；含氮螺杂环基，如“7-11元含氮螺杂环基”)通过氮原子与亚甲基连接。
根据IUPAC化合物命名的规则，本发明所述的稠环是指由两个或两个以上环状结构彼此共用两个相邻的原子(即共用一个键)连接起来形成的稠环结构。本发明所述的桥环是指由两个或两个以上环状结构彼此共用两个非相邻碳原子连接起来形成的桥环结构。本发明所述的螺环是指由两个或两个以上环状结构彼此共用一个碳原子连接起来形成的螺环结构。
本发明所述的“6-10元稠杂环基”，是指两个或两个以上环状结构彼此共用两个相邻的原子(即共用一个键)连接起来形成的至少含有一个杂原子的6-10个环原子的稠环结构，包括例如“6-10元含氮稠杂环基”等。具体实例包括但不仅限于：3-氮杂双环[3.1.0]己烷、3,6-二氮杂双环[3.2.0]庚烷、3,8-二氮杂双环[4.2.0]辛烷、3,7-二氮杂双环[4.2.0]辛烷、八氢吡咯并[3,4-c]吡咯、八氢吡咯并[3,4-b]吡咯、八氢吡咯并[3,4-b][1,4]噁嗪、八氢-1H-吡咯并[3,4-c]吡啶、八氢-1H-吡咯并[3,4-b]吡啶、八氢-1H-吡啶并[3,4-b][1,4]噁嗪、十氢-2,6-萘、四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔啉基、苯并[d][1,3]二氧杂环戊烯基、1,3-二氢异苯并呋喃基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、色满基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基等。
本发明所述的“7-9元桥杂环基”，是指任意两个环共用两个不相邻的原子形成的至少含有一个杂原子的7-9个环原子的桥环结构，所述的杂原子选自N、S、O、CO、SO和/或SO 2等。其中包括例如“6-9元桥杂环基”、“7-9元含氮桥杂环基”、“7-8元桥杂环基”、“8元桥杂环基”、“8元含氮桥杂环基”等。其实例包括但不限于：
Figure PCTCN2020088874-appb-000010
Figure PCTCN2020088874-appb-000011
Figure PCTCN2020088874-appb-000012
等。
本发明所述的“7-11元螺杂环基”，是指至少有两个环共享一个原子形成的至少含有一个杂原子的7-11个环原子的螺环结构，所述的杂原子选自N、S、O、CO、SO和/或SO 2等。其中包括例如“6-11元螺杂环基”、“7-11元含氮螺杂环基”、“7-10元螺杂环基”、“7-9元螺杂环基”、“7-8元螺杂环基”等。其实例包括但不仅限于：
Figure PCTCN2020088874-appb-000013
Figure PCTCN2020088874-appb-000014
Figure PCTCN2020088874-appb-000015
等。
本发明所述的“式(I’)化合物的药学上可接受的盐”中，式(I’)化合物与相应碱金属、其他金属、有机碱、无机酸、有机酸的分子比例可为任意值。
本发明所述的“药物组合物”，为药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
所述的药学上可接受的载体，包括但不仅限于：填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、表面活性剂、防腐剂、着色剂、矫味剂、芳香剂、泡腾剂、乳化剂、絮凝剂、反絮凝剂、抑菌剂、增溶剂。
本发明所述的肿瘤、癌症或癌，还包括原发器官、组织和/或任何其它位置中的转移，不管肿瘤转移的位置。
本发明所述的其他抗肿瘤治疗失败指的是采用其他抗肿瘤治疗，出现疾病进展或不能耐受。
本发明所述的“胸腺瘤”根据世界卫生组织(WHO)分类法(2015年第四版)包括A型、AB型、B1型、B2型、B3型。
本发明所述的“胸腺癌”根据WHO分类法(2015年第四版)分为以下几个亚型：胸腺鳞状细胞癌，胸腺基底细胞样癌，粘液表皮样癌，肉瘤样癌，腺癌，NUT癌等。本发明所述的胸腺癌包括恶性胸腺瘤。
本发明所述的“化疗”是化学药物治疗的简称，主要通过使用化学治疗药物杀灭癌细胞达到治疗的目的，所使用的化学药物主要为具有细胞毒性的药物。
本发明所述的“放疗”是指一种肿瘤治疗方法，即肿瘤放射治疗，主要利用放射线进行肿瘤局部治疗，所述的“放射线”包括放射性同位素产生的α、β、γ射线和各类x射线治疗机或加速器产生的x射线、电子线、质子束及其他粒子束等。
本发明所述的“靶向治疗”是指靶向药物通过识别肿瘤细胞的特异性蛋白而进行定位精准治疗的方法。
本发明所述的“免疫治疗”是指通过激活体内的免疫系统来控制或清除肿瘤细胞的一种治疗方法。
在本发明中，受试者或者患者可以是任何动物，优选地哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物。其中，特别优选的受试者为人。
本发明所述的“QD”是指每天给药一次。
本发明还提供治疗胸腺瘤的方法，其包括向需要此治疗的患者给予治疗有效量的式(I’)化合物、其药学上可接受的盐或其晶型，可以通过本领域中已知的任何常规和可接受的方式给药，治疗有效量根据患者的种族、性别、年龄、体重、医疗条件、疾病的类型、疾病的严重程度、施用途径和相关健康状况以及本领域技术人员已知的其他因素进行调整。
如本文中所使用的“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄、体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
本发明还提供式(I’)化合物与一种或多种其他治疗剂的组合物，可将这些其他治疗剂与式(1)化合物同时或相继给药，用于治疗胸腺瘤患者。
5、说明书附图
图1化合物1治疗前的CT放射影像图。
图2服用化合物1八个周期(约八个月)后的CT放射影像图。
图3服用化合物1后靶病灶肿瘤大小变化百分比，横坐标表示时间(试验研究天数)，其中C3D1表示第3周期第一天，C5D1表示第5周期第1天，以此类推，每一给药周期约28天，具体与实验例中给药方案相对应；纵坐标为肿瘤体积变化百分比。
图4化合物1晶型A的X-射线粉末衍射图谱(XRPD图谱)，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
具体实施方式
以下结合具体实施例及实验例对本发明的上述内容作进一步的详细说明。应理解，以下实施例和实验例仅用于说明本公开，但并不以此来限定本公开的保护范围。下面实施例中未注明具体条件者，按照常规条件或制造商建议的进行。所用药品或试剂未注明生产厂商者，均为可以通过市购获得的常规产品。
以下实施例或实验例中所用到的式(I’)化合物按照专利申请PCT/CN2014/095615中说明书实施例1的制备方法制备获得(即化合物1)。
化合物1的晶型A即为专利申请PCT/CN2018/124418中说明书中的式(I)化合物的晶型A，并在本说明书中引用了制备方法相关的内容。对于本申请中提到的化合物1的晶型A，其参数表征、性质试验等相关内容，参见专利申请PCT/CN2018/124418，并引用于本文中。
制备实施例：
化合物1的晶型A的制备方法
制备方法一：取5.0g化合物1，加入丙酮75mL，磁力搅拌下溶解立即析出白色固体，经搅拌5h后，抽滤，得白色粉末经35℃真空干燥16h后，所得固体经XRPD测试，为晶型A。
制备方法二：取500mg化合物1，加入异丙醇15mL，油浴80℃搅拌，溶解并且变的清澈(4.0h内)，自然降至室温(32℃)，析出白色固体，室温下继续搅拌12h，降温至15℃搅拌4.0h，抽滤，所得固体经45℃真空干燥16h，经XRPD、 1H-NMR分析，所得固体为晶型A。
制备方法三：取5.0g化合物1于100mL三口瓶中，加入仲丁醇75mL，油浴控温95℃，机械搅拌0.5h，溶解并且变的清澈。然后降温至油浴70℃，加入晶种(即制备方法一、二所得晶型A)约25mg，开始慢慢析出白色固体，继续降温至油浴60℃，恒温0.5h，降温至55℃，恒温0.5h，继续降至约20℃，搅拌1.5h，抽滤，甲基叔丁基醚淋 洗(2×10mL)，所得固体经65℃真空干燥24h， 1H-NMR检测显示无溶剂残留，经XRPD分析为晶型A。
制备方法四：
1)晶种制备：取40g化合物1和300g正戊醇，加热至75℃，搅拌桨转速R＝300r/min，约0.5h后原料开始溶解，完全溶解并且变的清澈后，继续保持75℃稳定0.5h。降低搅拌速率至R＝150r/min，澄清溶液在约0.5h内快速降温至55℃。到达55℃后，提高搅拌速率至R＝300r/min，继续以9℃/h速率降温直至5℃，体系缓慢混浊析出固体，到达5℃后恒温2小时，抽滤，所得固体即为晶种。
2)晶型A制备方法：将50g化合物1分散于300g正戊醇中，加热至85℃，完全溶解并且变的清澈，快速降温至58℃(85-58℃/h)，添加0.1g上述1)中所得晶种，恒温60min，此时体系缓慢混浊直至变为白色固体，以6℃/h速率缓慢降温直至5℃，继续恒温过夜，然后抽滤，所得固体放入真空干燥装置，100℃干燥6h，干燥所得固体经65℃真空干燥24h， 1H-NMR检测显示无溶剂残留，经XRPD分析为晶型A。
针对制备方法一至四得到的产品进行检测，晶型A纯度大于99.7％，单个最大杂质小于0.08％，几乎无溶剂残留。
XRPD测试
所用仪器：Bruker D2X射线粉末衍射仪。
X射线参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：1mm；扫描模式：连续；扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：19.8s；探测器角度：2.0度。
化合物I的晶型A在X-射线粉末衍射图示于图4中，该晶型在以下衍射2θ角度处有峰：6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°。
实验例式(I’)化合物对胸腺瘤的疗效
供试品：
化合物1晶型A的片剂。向化合物1晶型A加入适宜辅料制备成一定规格的片剂。
试验入组标准：
1.年龄18～70岁男性或女性受试者(包括18及70岁)；
2.经组织学或细胞学确诊的，且经标准治疗失败(疾病进展或不能耐受)或缺乏标准治 疗的局部晚期或转移性恶性胸腺瘤受试者；
3.受试者必须具有至少一处符合RECIST v1.1定义的可测量的病灶；
4.ECOG评分为0～1；
5.既往抗癌治疗或外科手术的所有急性毒性反应缓解至基线或≤1级(NCI-CTCAE v4.03版，脱发或研究者认为对受试者无安全风险的其它毒性除外)；
6.在首次给药前已经停止所有既往抗肿瘤治疗(包括化疗、放疗和免疫治疗等，不包括去势治疗)至少4周(其中亚硝基脲类或丝裂霉素停止治疗应≥6周，口服的乳腺癌内分泌治疗药物、小分子靶向治疗药物及抗肿瘤中药(汤药或中成药)至少停药2周)；
7.入组时受试者器官功能良好，且实验室检查数据符合下列标准：
·血常规：中性粒细胞绝对计数≥2.0×10 9/L(或大于研究中心实验室正常值下限)，血小板计数≥100×10 9/L，血红蛋白≥100g/L；
·肝功能：血清总胆红素≤1.5倍标准值上限(ULN)，AST和ALT≤1.5倍ULN；
·肾功能：CrCl≥60ml/min/1.73m 2(按照Cockcroft-Gault公式计算)；
8.经研究者判定，预期受试者寿命≥12周；
9.有生育能力的男性或女性受试者必须同意在研究期间和末次研究用药30天内使用有效的避孕方法，例如双重屏障式避孕方法、避孕套、口服或注射避孕药物、宫内节育器等；
10.研究开始前，受试者必须提供书面的知情同意。
病史：
一名36岁男性患者，2015年7月下旬患者因“咳嗽、咳痰、腹胀、腹泻、口干”就诊，PET-CT检查显示：左侧胸膜多发增厚并代谢活性增高，双肺多发斑片斑点影及微结节。行胸膜肿物穿刺活检示：B1型(富于淋巴细胞型)胸腺瘤。7月31日于胸外科行胸腔镜辅助下左侧开胸探查、胸腺瘤切左肺上叶楔形切除、部分心包切除、胸膜剥落、胸腔闭式引流术。术后病理：胸腺瘤，B2型，侵及心包壁层、肺组织，以及脏层、壁层、膈处胸膜。
术后辅助：2015年9月16日-12月10日行紫杉醇+洛铂术后辅助化疗4周期。2018年4月13日、5月17日行紫杉醇+顺铂+重组人血管内皮抑制素方案化疗2周期。
治疗过程：
2018年6月26日入院诊断：胸腺瘤，左肺及胸膜转移；中耳炎；双肺炎。主诉：双耳鸣，偶有咳嗽、咳痰，咳黄色黏痰，痰量较多。6月28日予以哌拉西林钠他唑巴坦纳抗感染治疗，7月3日开始联合氟康唑抗真菌治疗，7月11日起予以莫西沙星+伏立康唑抗感染治疗，7月16日复查炎症好转。
2018年7月19日完善入组前基线检查。查胸腹盆增强CT示：胸腺瘤、胸膜剥脱术后改变；左前上纵隔软组织密度影；两肺感染性病变；ECOG评分≤1，经研究者判断，预计生存期≥12周；生命体征、体格检查、心电图、超声心动图及实验室安全性检查结果均符合标准。
目标病灶的评价标准
Figure PCTCN2020088874-appb-000016
给药方案：
1)80mg QD连续给药3个周期(即第1-3周期)；
2)160mg QD连续给药4个周期(即第4-7周期)；
3)240mg QD连续给药3个周期(即第8-10周期)；
4)320mg QD连续给药3个周期(即第11-13周期)。
不良事件:
不良事件包括呕吐(1级)，将服药时间由空腹服药改为餐后服药后症状消失，临床可控。未发生严重不良事件(SAE)及因不良事件导致暂停给药、剂量下调及提前出组的情况。
疗效：
本次为二线治疗恶性胸腺瘤，治疗过程经历了3次剂量上调，目前使用剂量为320mg QD。该患者目前已经稳定了12个月的时间，并且如图3所示，在第12周期给药结束时，肿瘤经线和已经较基线缩小了38.6％，目标病灶达到了部分缓解(PR)的标准。

Claims (15)

  1. 式(I’)化合物、其药学上可接受的盐或其晶型在制备用于治疗胸腺瘤的药物中的用途，
    Figure PCTCN2020088874-appb-100001
    其中，
    A 1和A 2分别独立地为氮；
    R 1选自C 1-6烷基；
    R 2选自C 1-6烷基；
    R 3和R 5分别独立地选自卤素或氢，且R 3和R 5至少一个为卤素；
    R 4选自任选被Q 2取代的5-6元含氮杂环基、6-10元含氮稠杂环基、7-9元含氮桥杂环基或7-11元含氮螺杂环基；
    Q 2选自氨基，羟基，卤素，三氟甲基，氰基，C 1-6烷氧基，二C 1-6烷基氨基，或任选被取代基取代的C 1-6烷基、3-6元环烷基、3-6元杂环基或7-9元桥杂环基，所述取代基选自氨基、羟基、卤素、三氟甲基、氰基、C 1-6烷基、C 1-6烷氧基、3-6元环烷基；
    n选自0、1。
  2. 如权利要求1所述的用途，其中，所述化合物具有下述式(I”)的结构，
    Figure PCTCN2020088874-appb-100002
    其中，
    A 1和A 2分别独立地为氮；
    R 1选自C 1-4烷基；
    R 2选自C 1-4烷基；
    R 3和R 5分别独立地选自卤素；
    R 4选自任选被Q 2取代的5-6元含氮杂环基、6-10元含氮稠杂环基、7-9元含氮桥杂环基或7-11元含氮螺杂环基，
    Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基、5-6元杂环基或7-9元桥杂环基。
  3. 如权利要求2所述的用途，其中
    A 1和A 2分别独立地为氮；
    R 1为异丙基；
    R 2为甲基；
    R 3和R 5各自是氟；
    R 4选自任选被Q 2取代的5-6元含氮杂环基，其中Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基、6元杂环基或8元桥杂环基。
  4. 如权利要求3所述的用途，其中
    R 4选自任选被Q 2取代的含1-2个氮原子的5-6元含氮杂环基，所述5-6元含氮杂环基通过氮原子与通式(I”)中的亚甲基连接，其中Q 2选自氨基、羟基、三氟甲基、氰基、C 1-4烷基、C 1-4烷氧基或8元含氮桥杂环基。
  5. 如权利要求4所述的用途，其中
    R 4选自任选被Q 2取代的
    Figure PCTCN2020088874-appb-100003
    其中Q 2选自C 1-4烷基或8元含氮桥杂环基。
  6. 如权利要求1所述的用途，所述化合物选自下述化合物：
    Figure PCTCN2020088874-appb-100004
    Figure PCTCN2020088874-appb-100005
    Figure PCTCN2020088874-appb-100006
    Figure PCTCN2020088874-appb-100007
  7. 如权利要求1-6任一项所述的用途，所述化合物选自下述化合物：
    Figure PCTCN2020088874-appb-100008
  8. 如权利要求1-7任一项所述的用途，所述的胸腺瘤为晚期和/或转移性胸腺瘤。
  9. 如权利要求1-7任一项所述的用途，所述的胸腺瘤为其他抗肿瘤治疗失败的胸腺瘤。
  10. 如权利要求1-7任一项所述的用途，所述的胸腺瘤为胸腺癌。
  11. 如权利要求1-10任一项所述的用途，其中，式(I’)化合物、其药学上可接受的盐或其晶型单独施用或与一种或多种其他治疗剂组合施用。
  12. 一种药物组合物在制备用于治疗胸腺瘤的药物中的用途，所述组合物包括式(I’)化合物、其药学上可接受的盐或其晶型与药学上可接受的载体，任选地，还包括一种或多种其他治疗剂。
  13. 如权利要求11或12所述的用途，其中，所述的其他治疗剂选自抗代谢物抗肿瘤药、生长因子抑制剂抗肿瘤药、抗体类抗肿瘤药、有丝分裂抑制剂抗肿瘤药、激素类抗肿瘤药、烷化剂类抗肿瘤药、金属铂类抗肿瘤药、拓扑异构酶抑制剂抗肿瘤药、免疫抑制类抗肿瘤药、嘌呤类似物抗肿瘤药、抗生素类抗肿瘤药、激酶抑制剂类抗肿瘤药、靶向治疗药物。
  14. 如权利要求1-13任一项所述的用途，其中，所述的晶型选自式(I’)化合物的游离体晶型。
  15. 如权利要求1-14任一项所述的用途，其中，所述的晶型选自下述化合物的晶型A， 所述晶型A在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱在6.6±0.2°、10.0±0.2°、13.2±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°处有特征峰；
    优选地，所述晶型A在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°、30.4±0.2°处有特征峰；
    优选地，所述晶型A在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°处有特征峰；
    优选地，所述晶型A具有基本上如图4所示的使用Cu-Kα辐射获得的X-射线粉末衍射图；
    Figure PCTCN2020088874-appb-100009
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